Bleeding After Free Flap-Based Breast Reconstruction: A NSQIP Analysis.

BACKGROUND: Despite limited oncologic benefit for women without an increased risk for breast cancer, the rates of contralateral prophylactic mastectomy (CPM) have increased. Patients undergoing CPM are more likely to undergo bilateral and immediate breast reconstruction. This study assessed the relationship between the timing and laterality of free flap-based breast reconstruction and the risk of postoperative bleeding complications. METHODS: Women undergoing postmastectomy free-flap based breast reconstruction from 2010 to 2015 were identified using the National Surgical Quality Improvement Program (NSQIP) dataset. Patients were categorized according to reconstructive laterality and timing. Modified Poisson regression was used to assess the risk of postoperative bleeding and complications across reconstructive procedures. RESULTS: Of the 4,133 patients undergoing free flap-based breast reconstruction, 12% (n = 494) experienced postoperative bleeding complications. Bilateral immediate reconstruction was associated with the highest incidence of bleeding (16.6%, n = 188), followed by bilateral delayed (12.8%, n = 58), unilateral immediate (10%, n = 142), and unilateral delayed reconstruction (9.4%, n = 106). Among patients undergoing immediate reconstruction, bilateral, rather than unilateral, reconstruction was associated with a significantly elevated risk of bleeding complications (RR [rate ratio] = 1.58; 95% CI [confidence interval] =1.19, 2.10; p = 0.0002). Furthermore, immediate bilateral reconstruction was associated with a significantly higher rate of return to the operating room (RR =1.39; 95% CI =1.06, 1.82; adjusted p = 0.009) when compared with a unilateral procedure. CONCLUSION: Patients undergoing immediate bilateral free flap-based breast reconstruction may be at an increased risk for experiencing acute postoperative bleeding complications and a return to the operating room. Patients undergoing CPM and considering immediate reconstruction should be counseled regarding the increased morbidity of a bilateral reconstructive procedure.

Identifying Predictors of Time to Soft-Tissue Reconstruction following Open Tibia Fractures.

BACKGROUND: Controversy remains regarding the optimal timing of soft-tissue coverage following severe lower extremity trauma. This study identifies nationwide practice patterns and factors associated with discrepancies in time to first flap surgery following open tibia fractures. METHODS: A retrospective analysis was performed on the National Trauma Databank from 2008 to 2015 to identify patients who presented with an open tibia fracture and underwent subsequent flap reconstruction. A least absolute shrinkage and selection operator algorithm was performed, revealing those factors most significantly associated with differences in time to flap surgery from hospitalization. RESULTS: A total of 3297 patients were included in the analysis. Mean ± SD and median times to first flap surgery were 230.1 ± 246.7 hours and 169.1 hours, respectively. Older age, nonwhite race, treatment in the South, and non-private insurance status were all independently associated with an increased time to flap surgery. In addition, more surgical débridements; a higher Injury Severity Score and/or Abbreviated Injury Scale score; and a nerve, vascular, and/or crush injury were independent predictors of an increased time to flap surgery. CONCLUSIONS: Most patients who present with open tibia fractures requiring soft-tissue coverage undergo flap reconstruction after the historical 72-hour window. Specific sociodemographic and clinical factors were independently predictive of an increased time to flap surgery. These findings suggest that not all patients in the United States are receiving the same level of care in lower extremity trauma reconstruction, emphasizing the need to develop more explicit national standards. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Antibiotic-induced changes in the microbiota disrupt redox dynamics in the gut.

How host and microbial factors combine to structure gut microbial communities remains incompletely understood. Redox potential is an important environmental feature affected by both host and microbial actions. We assessed how antibiotics, which can impact host and microbial function, change redox state and how this contributes to post-antibiotic succession. We showed gut redox potential increased within hours of an antibiotic dose in mice. Host and microbial functioning changed under treatment, but shifts in redox potentials could be attributed specifically to bacterial suppression in a host-free ex vivo human gut microbiota model. Redox dynamics were linked to blooms of the bacterial family Enterobacteriaceae. Ecological succession to pre-treatment composition was associated with recovery of gut redox, but also required dispersal from unaffected gut communities. As bacterial competition for electron acceptors can be a key ecological factor structuring gut communities, these results support the potential for manipulating gut microbiota through managing bacterial respiration.

Lymphovenous Anastomosis for the Treatment of Chylothorax in Infants: A Novel Microsurgical Approach to a Devastating Problem.

With the expanding horizon of microsurgical techniques, novel treatment strategies for lymphatic abnormalities are increasingly reported. Described in this article is the first reported use of lymphovenous anastomosis surgery to manage recalcitrant chylothoraces in infants. Chylothorax is an increasingly common postoperative complication after pediatric cardiac surgery, with a reported incidence of up to 9.2 percent in infants. Although conservative nutritional therapy has a reported 70 percent success rate in this patient population, failed conservative management leading to persistent chylothorax is associated with a significant risk of multisystem complications and mortality. Once conservative medical strategies are deemed unsuccessful, surgical or radiologic interventions, such as percutaneous thoracic duct embolization or ligation, are often attempted. However, these procedures lack high-level evidence in the infant population and remain a challenge, given the small size of the lymphatic vessels. As such, we report our experience with performing lymphovenous anastomoses in two infants who had developed refractory chylothoraces secondary to thoracic duct injury following cardiac surgery for congenital cardiac anomalies. In addition, this article reviews the relevant pathophysiology of chylothoraces, current treatment algorithm following failed conservative management, and potential role of the microsurgeon in the multidisciplinary management of this life-threatening problem. As part of the evolving microsurgery frontier, physiologic operations, such as lymphovenous anastomosis, may have a considerable role in the management of refractory pediatric chylothoraces. In our experience, lymphovenous anastomosis can restore normal lymphatic circulation within 1 to 2 weeks, liberate patients from mechanical ventilation, and enable expeditious return to enteral feeding. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Muscle versus Fasciocutaneous Free Flaps in Lower Extremity Traumatic Reconstruction: A Multicenter Outcomes Analysis.

BACKGROUND: Clinical indications are expanding for the use of fasciocutaneous free flaps in lower extremity traumatic reconstruction. The authors assessed the impact of muscle versus fasciocutaneous free flap coverage on reconstructive and functional outcomes. METHODS: A multicenter retrospective review was conducted on all lower extremity traumatic free flaps performed at Duke University (1997 to 2013) and the University of Pennsylvania (2002 to 2013). Muscle and fasciocutaneous flaps were compared in two subgroups (acute trauma and chronic traumatic sequelae), according to limb salvage, ambulation time, and flap outcomes. RESULTS: A total of 518 lower extremity free flaps were performed for acute traumatic injuries (n = 238) or chronic traumatic sequelae (n = 280). Muscle (n = 307) and fasciocutaneous (n = 211) flaps achieved similar cumulative limb salvage rates in acute trauma (90 percent versus 94 percent; p = 0.56) and chronic trauma subgroups (90 percent versus 88 percent; p = 0.51). Additionally, flap choice did not impact functional recovery (p = 0.83 for acute trauma; p = 0.49 for chronic trauma). Flap groups did not differ in the rates of flap thrombosis, flap salvage, flap loss, or tibial nonunion requiring bone grafting. Fasciocutaneous flaps were more commonly reelevated for subsequent orthopedic procedures (p < 0.01) and required fewer secondary skin-grafting procedures (p = 0.01). Reconstructive and functional outcomes remained heavily influenced by injury severity. CONCLUSIONS: Muscle and fasciocutaneous free flaps achieved comparable rates of limb salvage and functional recovery. Flap selection should be guided by defect characteristics and reconstructive needs. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

The Impact of Autologous Breast Reconstruction on Body Mass Index Patterns in Breast Cancer Patients: A Propensity-Matched Analysis.

BACKGROUND: Weight gain is common in breast cancer patients and increases the risk of recurrence and mortality. The authors assessed the impact of autologous breast reconstruction on body mass index patterns after diagnosis in mastectomy patients. METHODS: Women undergoing therapeutic mastectomy at the authors' institution from 2008 to 2010 were identified. Patients undergoing no breast reconstruction or autologous breast reconstruction were propensity-matched by age at diagnosis, baseline obesity, mastectomy laterality, and adjuvant therapies. Multivariable regression was used to estimate covariate associations with percentage body mass index change and percentage body mass index change greater than 5.0 percent at 1 to 4 years after diagnosis. RESULTS: Of 524 total patients, 80 propensity-matched pairs were identified. In multivariable regression, women undergoing immediate autologous breast reconstruction had reduced body mass index changes after diagnosis, compared with nonreconstruction patients, at 1 year (ß = -5.25 percent; p < 0.01), 2 years (ß = -8.78 percent; p < 0.01), and 3 years (ß = -7.21 percent; p < 0.01). After 4 years, all autologous reconstruction was predictive of reduced body mass index changes (ß = -3.54 percent; p = 0.02). Higher body mass index increases were observed among women who were leaner at diagnosis (p < 0.01 at 1 year) and received chemotherapy (p = 0.02 at 3 years; p = 0.04 at 4 years). CONCLUSIONS: Women undergoing autologous breast reconstruction gained less weight after diagnosis than nonreconstruction patients. Normal baseline body mass index and chemotherapy were predictive of greater body mass index increases. These findings may guide targeted weight management strategies in high-risk patients to maximize survival rates. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Association Between Targeted HER-2 Therapy and Breast Reconstruction Outcomes: A Propensity Score-Matched Analysis.

BACKGROUND: Current treatment for HER-2+ breast cancer includes chemotherapy and targeted HER-2 therapy with trastuzumab and/or pertuzumab. Evidence is lacking on the safety of breast reconstructive operations in these patients. We hypothesized that targeted HER-2 therapy was not associated with post-mastectomy reconstructive outcomes. STUDY DESIGN: Women receiving chemotherapy and post-mastectomy reconstruction at Duke University Medical Center from 2006 to 2016 were retrospectively identified. Patients receiving targeted HER-2 therapy with trastuzumab and/or pertuzumab within 6 weeks before breast reconstruction were propensity score-matched 1:1 to patients who did not receive targeted HER-2 therapy, based on the following factors: age, obesity, diabetes, tobacco use, receipt of neoadjuvant chemotherapy, chemotherapy regimen, and radiation therapy. Primary study outcomes included the occurrence of hematoma, seroma, infection, wound breakdown, mastectomy skin flap necrosis, and postoperative flap thrombosis. RESULTS: A total of 481 women were identified, resulting in 107 propensity score-matched pairs. Administration of combined trastuzumab and pertuzumab therapy before breast reconstruction was independently associated with increased risk of postoperative wound breakdown requiring operative intervention for closure, compared with patients not undergoing targeted HER-2 therapy (odds ratio 65.29; 95% CI 1.63 to 2,611.50; p = 0.03). In addition, larger tumor size (2 to 5 cm) was significantly associated with a reduced risk of postoperative wound breakdown, compared with smaller tumors (<2 cm) (odds ratio 0.41; 95% CI 0.19 to 0.87; p = 0.02). Single-agent targeted HER-2 therapy with trastuzumab was not significantly associated with reconstructive complications. CONCLUSIONS: Our study suggests that trastuzumab therapy in conjunction with breast reconstructive operation is not associated with reconstructive complications, and breast reconstruction does not need to be delayed due to the administration of trastuzumab. Future studies are needed to evaluate the impact of pertuzumab on surgical outcomes.

Assessing the effort associated with teaching residents.

BACKGROUND: Intraoperative resident education is an integral mission of academic medical centers and serves as the basis for training the next generation of surgeons. The actual effort associated with teaching residents is unknown as it pertains to additional operative time. Using a large validated multi-institutional dataset, this study aims to quantify the effect of having a resident present in common plastic surgery procedures on operative time. Future directions for developing standardized methods to record and report teaching time are proposed, which can help inform prospective studies. STUDY DESIGN: The 2006-2012 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried to identify seven isolated plastic surgical procedures that were categorized based on resident involvement and supervision. Linear regression models were used to calculate the difference in operative time with respect to resident participation while controlling for patient and operative factors. RESULTS: Resident involvement was associated with longer operative times for muscle flap trunk procedures (53 min, 95% CI = [25, 80], p-value = 0.0002) and breast reconstruction procedures with a latissimus dorsi flap (55 min, 95% CI = [22, 88], p-value = 0.001). For six of the seven surgeries evaluated, resident involvement was associated with longer operative times, as compared to no resident involvement. CONCLUSION: Resident involvement is associated with an increase in operative time for certain plastic surgery procedures. This finding underscores the need for a mechanism to quantify the time and effort that the attending surgeons allocate toward intraoperative resident education. Further study is also necessary to determine the causal impact on patient care.

Breast Cancer after Augmentation: Oncologic and Reconstructive Considerations among Women Undergoing Mastectomy.

BACKGROUND: Breast augmentation with subglandular versus subpectoral implants may differentially impact the early detection of breast cancer and treatment recommendations. The authors assessed the impact of prior augmentation on the diagnosis and management of breast cancer in women undergoing mastectomy. METHODS: Breast cancer diagnosis and management were retrospectively analyzed in all women with prior augmentation undergoing therapeutic mastectomy at the authors' institution from 1993 to 2014. Comparison was made to all women with no prior augmentation undergoing mastectomy in 2010. Subanalyses were performed according to prior implant placement. RESULTS: A total of 260 women with (n = 89) and without (n = 171) prior augmentation underwent mastectomy for 95 and 179 breast cancers, respectively. Prior implant placement was subglandular (n = 27) or subpectoral (n = 63) (For five breasts, the placement was unknown). Breast cancer stage at diagnosis (p = 0.19) and detection method (p = 0.48) did not differ for women with and without prior augmentation. Compared to subpectoral augmentation, subglandular augmentation was associated with the diagnosis of invasive breast cancer rather than ductal carcinoma in situ (p = 0.01) and detection by self-palpation rather than screening mammography (p = 0.03). Immediate two-stage implant reconstruction was the preferred reconstructive method in women with augmentation (p < 0.01). CONCLUSIONS: Breast cancer stage at diagnosis was similar for women with and without prior augmentation. Among women with augmentation, however, subglandular implants were associated with more advanced breast tumors commonly detected on palpation rather than mammography. Increased vigilance in breast cancer screening is recommended among women with subglandular augmentation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Preoperative Platelet Count Predicts Lower Extremity Free Flap Thrombosis: A Multi-Institutional Experience.

BACKGROUND: Thrombocytosis in patients undergoing lower extremity free tissue transfer may be associated with increased risk of microvascular complications. This study assessed whether preoperative platelet counts predict lower extremity free flap thrombosis. METHODS: All patients undergoing lower extremity free tissue transfer at Duke University from 1997 to 2013 and at the University of Pennsylvania from 2002 to 2013 were retrospectively identified. Logistic regression was used to assess whether preoperative platelet counts independently predict flap thrombosis, controlling for baseline and operative factors. RESULTS: A total of 565 patients underwent lower extremity free tissue transfer, with an overall flap thrombosis rate of 16 percent (n = 91). Elevated preoperative platelet counts were independently associated with both intraoperative thrombosis (500 ± 120 versus 316 ± 144 × 10/liter; p < 0.001) and postoperative thrombosis (410 ± 183 versus 320 ± 143 × 10/liter; p = 0.040) in 215 patients who sustained acute lower extremity trauma within 30 days before reconstruction. In acute trauma patients, preoperative platelet counts predicted a four-fold increased risk of intraoperative thrombosis (cutoff value, 403 × 10/liter; OR, 4.08; p < 0.001) and a two-fold increased risk of postoperative thrombosis (cutoff value, 361 × 10/liter; OR, 2.16; p = 0.005). In patients who did not sustain acute trauma, preoperative platelet counts predicted a four-fold increased risk of intraoperative thrombosis (cutoff value, 352 × 10/liter; OR, 3.82; p = 0.002). CONCLUSIONS: Acute trauma patients with elevated preoperative platelet counts are at increased risk for lower extremity free flap complications. Prospective evaluation is warranted for guiding risk stratification and targeted treatment strategies. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Vascular considerations in foot and ankle free tissue transfer: Analysis of 231 free flaps.

OBJECTIVE: Successful foot and ankle soft tissue reconstruction is dependent on a clear understanding of the vascular supply to the foot. The aim of this study was to identify risk factors for reconstructive failure following foot and ankle free tissue transfer. METHODS: The authors retrospectively reviewed their 17-year institutional experience with 231 foot and ankle free flaps performed in 225 patients to determine predictors of postoperative foot ischemia and flap failure. Postoperative foot ischemia was defined as ischemia resulting in tissue necrosis, separate from the reconstruction site. RESULTS: Six (3%) patients developed postoperative foot ischemia, and 28 (12%) patients experienced flap failure. Chronic ulceration (P = 0.02) and an elevated preoperative platelet count (P = 0.04) were independent predictors of foot ischemia. The presence of diabetes was predictive of flap failure (P = 0.05). Flap failure rates were higher in the setting of an abnormal preoperative angiogram (P = 0.04), although the type and number of occluded arteries did not influence outcome. Foot ischemia was more frequent following surgical revascularization in conjunction with free tissue transfer and the use of the distal arterial bypass graft for flap anastomosis (P < 0.01). Overall, no differences were observed in foot ischemia (P = 0.17) and flap failure (P = 0.75) rates when the flap anastomosis was performed to the diseased artery noted on angiography, compared with an unobstructed native tibial artery. CONCLUSIONS: Foot and ankle free tissue transfer may be performed with a low incidence of foot ischemia. Patients with diabetes, chronic ulceration, and an elevated preoperative platelet count are at higher risk for reconstructive failure. © 2015 Wiley Periodicals, Inc. Microsurgery 36:276-283, 2016.

Microvascular Anastomoses Using End-to-End versus End-to-Side Technique in Lower Extremity Free Tissue Transfer.

BACKGROUND: The decision to perform an end-to-end (ETE) or end-to-side (ETS) arterial anastomosis in lower extremity free tissue transfer has not been thoroughly evaluated in a large multisurgeon setting. The authors compared the reconstructive outcomes of lower extremity free flaps with ETE and ETS arterial anastomoses. METHODS: The authors retrospectively reviewed their 17-year institutional experience with lower extremity free flaps to determine whether ETE or ETS arterial anastomoses were associated with foot ischemic complications and flap failure. RESULTS: From 1996 to 2013, 398 patients underwent 413 lower extremity free flaps with ETE (66%) or ETS (34%) arterial anastomoses. The incidence of postoperative foot ischemia was 2% (n = 8). The flap failure rate was 11% (n = 45). The ETS technique was preferred in patients with fewer intact vessels to the foot (32% ETS for three-vessel runoff, 36% ETS for two-vessel runoff, and 50% ETS for single-vessel runoff) and when an intact recipient vessel was selected for anastomosis (60% ETS for intact vessel vs. 25% ETS for distally occluded vessel). No differences were observed in the foot ischemia (p = 0.45) and flap failure rates (p = 0.59) for ETE versus ETS arterial anastomoses. In subset analyses, the incidence of foot ischemia did not differ for either technique in the context of impaired vascular runoff or recipient vessel selection. CONCLUSION: No advantage was noted for ETE or ETS arterial anastomoses based on reconstructive outcomes. The choice of anastomotic technique in lower extremity free tissue transfer should be based on patient factors and the clinical circumstances encountered.

In vivo detection of SERS-encoded plasmonic nanostars in human skin grafts and live animal models.

Surface-enhanced Raman scattering (SERS)-active plasmonic nanomaterials have become a promising agent for molecular imaging and multiplex detection. Among the wide variety of plasmonics-active nanoparticles, gold nanostars offer unique plasmon properties that efficiently induce strong SERS signals. Furthermore, nanostars, with their small core size and multiple long thin branches, exhibit high absorption cross sections that are tunable in the near-infrared region of the tissue optical window, rendering them efficient for in vivo spectroscopic detection. This study investigated the use of SERS-encoded gold nanostars for in vivo detection. Ex vivo measurements were performed using human skin grafts to investigate the detection of SERS-encoded nanostars through tissue. We also integrated gold nanostars into a biocompatible scaffold to aid in performing in vivo spectroscopic analyses. In this study, for the first time, we demonstrate in vivo SERS detection of gold nanostars using small animal (rat) as well as large animal (pig) models. The results of this study establish the usefulness and potential of SERS-encoded gold nanostars for future use in long-term in vivo analyte sensing.

Role of platelet inhibition in microvascular surgery.

Thrombosis remains a significant complication of microvascular free tissue transfer. Recent discoveries in the field of vascular biology have led to a greater understanding of thrombogenesis and the pivotal role that platelets play in the formation of a clot. However, current antithrombotic strategies in the clinical practice of free tissue transfer have not typically focused on platelet inhibition. Decades of cardiovascular clinical trials have delineated the essential role of platelet inhibitor therapy in patients with acute coronary syndromes and those undergoing percutaneous coronary interventions. Understanding the current treatment guidelines for antiplatelet therapy across the spectrum of patients with coronary heart disease may provide insights into their use in the prevention and treatment of thrombosis in microvascular surgery. In this review, we examine the current antiplatelet agents in clinical use and discuss the potential role of platelet inhibition in free flap surgery, particularly in the setting of repeated microvascular thrombosis.

Bioburden after Staphylococcus aureus inoculation in type 1 diabetic rats undergoing internal fixation.

SUMMARY: Fracture stabilization in the diabetic patient is associated with higher complication rates, particularly infection and impaired wound healing, which can lead to major tissue damage, osteomyelitis, and higher amputation rates. With an increasing prevalence of diabetes and an aging population, the risks of infection of internal fixation devices are expected to grow. Although numerous retrospective clinical studies have identified a relationship between diabetes and infection, currently there are few animal models that have been used to investigate postoperative surgical-site infections associated with internal fixator implantation and diabetes. The authors therefore refined the protocol for inducing hyperglycemia and compared the bacterial burden in controls to pharmacologically induced type 1 diabetic rats after undergoing internal fracture plate fixation and Staphylococcus aureus surgical-site inoculation. Using an initial series of streptozotocin doses, followed by optional additional doses to reach a target blood glucose range of 300 to 600 mg/dl, the authors reliably induced diabetes in 100 percent of the rats (n = 16), in which a narrow hyperglycemic range was maintained 14 days after onset of diabetes (mean ± SEM, 466 ± 16 mg/dl; coefficient of variation, 0.15). With respect to their primary endpoint, the authors quantified a significantly higher infectious burden in inoculated diabetic animals (median, 3.2 × 10 colony-forming units/mg dry tissue) compared with inoculated nondiabetic animals (7.2 × 10 colony-forming units/mg dry tissue). These data support the authors' hypothesis that uncontrolled diabetes adversely affects the immune system's ability to clear Staphylococcus aureus associated with internal hardware.

An algorithmic approach for managing orthopaedic surgical wounds of the foot and ankle.

BACKGROUND: Wound breakdown after orthopaedic foot and ankle surgery may necessitate secondary soft tissue coverage. The foot and ankle region is challenging to reconstruct for orthopaedic and plastic surgeons owing to its complex bony anatomy and unique functional demands. Therefore, identifying strategies for plastic surgery of these wounds may help guide surgeons in defining the best treatment plan. QUESTIONS/PURPOSES: We evaluated our current algorithmic approach for managing orthopaedic surgical wounds of the foot and ankle with respect to whether (1) prophylactic or simultaneous soft tissue coverage affected wound-healing complications (secondary plastic surgery, orthopaedic hardware removal, malunion, further orthopaedic surgery, ultimate failure) and (2) postoperative referral for soft tissue management was associated with wound location, size, and orthopaedic procedure. METHODS: We retrospectively reviewed 112 patients who underwent elective orthopaedic foot or ankle surgery and required concomitant plastic surgery at our institution. Study end points included secondary plastic surgery procedures, hardware removal for infection, foot or ankle malunion, further orthopaedic surgery, and wound-healing failure as defined by a chronic nonhealing wound or need for amputation. Minimum followup was 0.6 months (mean, 24.9 months; range, 0.6-197 months). Four patients were lost to complete followup. We developed an algorithm that centers on two critical points of care: preoperative evaluation by the orthopaedic surgeon and evaluation and treatment by the plastic surgeon after referral. RESULTS: Compared with postoperative intervention, prophylactic or simultaneous soft tissue coverage did not lead to differences in frequency of secondary plastic surgery procedures (p = 0.55), hardware removal procedures (p = 0.13), malunions (p = 0.47), further orthopaedic surgery (p = 0.48), and ultimate failure (p = 0.27). Patients referred postoperatively for soft tissue management most frequently had dorsal ankle wounds (p < 0.001) of smaller size (p = 0.03), most commonly associated with total ankle arthroplasty (p = 0.004). CONCLUSIONS: Using our algorithmic approach, prophylactic or simultaneous soft tissue coverage did not improve the study end points. In addition, unexpected postoperative wound breakdown necessitating a plastic surgery consultation most commonly occurred on the dorsal ankle after total ankle arthroplasty. Our algorithm facilitates early identification of skin instability and enables prompt soft tissue coverage before or concurrently with orthopaedic procedures. The effect of prophylactic or simultaneous soft tissue coverage on postoperative wound healing requires further investigation. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.

Development of polyploidy of scale-building cells in the wings of Manduca sexta.

The developing wings of butterflies and moths are composed of two epithelial monolayers. Each epithelial sheet is made up of two kinds of cells, diploid cells that make up the epidermal surface and body of the wing, and large polyploid cells that become the scale-building cells whose cytoplasmic projections develop into the scales that will cover the adult wing and bear the pigment pattern. We studied the development of polyploidization of the scale-building cells during the pupal stage of the tobacco hornworm moth, Manduca sexta. The endomitotic divisions of the presumptive scale-building cells and the mitotic divisions of the diploid epithelial cells begin on day 3 of the pupal stage and continue until day 7. We show that scales of different colors and positions on the wing differ in size, and that the size of the scale is proportional to the ploidy of the scale-building cell. Scale-building cells are arranged in irregular rows and within each row there is an alternation of ploidy levels, with the lower ploidy cells giving rise to the underscales and the higher ploidy cells giving rise to the cover scales that carry the color pattern. Along the wing there is a proximo-distal decreasing gradient of average ploidy and scale size. Scale-building cells of high ploidy are surrounded by fewer epidermal cells than those of low ploidy. This inverse relationship is known as Henke's compensation principle, which posits that the number of endomitoses of a pre-polyploid cell and the number of mitotic divisions of its diploid daughter cell add up to a constant. We show that the inverse relationship fits the predictions of the compensation principle and does not fit constraints imposed by packing density, and we discuss mechanisms that could give rise to the inverse relationship.

Bevacizumab-induced alterations in vascular permeability and drug delivery: a novel approach to augment regional chemotherapy for in-transit melanoma.

PURPOSE: To investigate whether the systemically administered anti-VEGF monoclonal antibody bevacizumab could improve regional chemotherapy treatment of advanced extremity melanoma by enhancing delivery and tumor uptake of regionally infused melphalan (LPAM). EXPERIMENTAL DESIGN: After treatment with systemic bevacizumab or saline, changes in vascular permeability were determined by spectrophotometric analysis of tumors infused with Evan's blue dye. Changes in vascular structure and tumor hemoglobin-oxygen saturation HbO(2) were determined by intravital microscopy and diffuse reflectance spectroscopy, respectively. Rats bearing the low-VEGF secreting DM738 and the high-VEGF secreting DM443 melanoma xenografts underwent isolated limb infusion (ILI) with melphalan (LPAM) or saline via the femoral vessels. The effect of bevacizumab on terminal drug delivery was determined by immunohistochemical analysis of LPAM-DNA adducts in tumor tissues. RESULTS: Single-dose bevacizumab given three days before ILI with LPAM significantly decreased vascular permeability (50.3% in DM443, P < 0.01 and 35% in DM738, P < 0.01) and interstitial fluid pressure (57% in DM443, P < 0.01 and 50% in DM738, P = 0.01). HbO(2) decreased from baseline in mice following treatment with bevacizumab. Systemic bevacizumab significantly enhanced tumor response to ILI with LPAM in two melanoma xenografts, DM443 and DM738, increasing quadrupling time 37% and 113%, respectively (P = 0.03). Immunohistochemical analyses of tumor specimens showed that pretreatment with systemic bevacizumab markedly increased LPAM-DNA adduct formation. CONCLUSIONS: Systemic treatment with bevacizumab before regional chemotherapy increases delivery of LPAM to tumor cells and represents a novel way to augment response to regional therapy for advanced extremity melanoma.